Penn Vet Study Reveals Salmonella’s Hideout Strategy

The body’s innate immune system is a first line of defense, intent on sensing invading pathogens and wiping them out before they can cause harm. It should not be surprising then that bacteria have evolved many ways to specifically evade and overcome this sentry system in order to spread infection.

A study led by researchers in the University of Pennsylvania’s School of Veterinary Medicine now reveals how some Salmonella bacteria hide from the immune system, allowing them to persist and cause systemic infection. The findings could help researchers craft a more effective vaccine against Salmonella.

“Many of the same signals that are present in harmless bacteria are also present in pathogenic bacteria,” Brodsky said. “One of the big unanswered questions is how does the innate immune system distinguish between the two? And, conversely, how have pathogenic bacteria evolved to get around the immune response?”

The Penn study addresses both questions, focusing on a component of the innate immune response called the inflammasome. Consisting of a complex of proteins that triggers the release of signaling molecules, the inflammasome serves to recruit other components of the immune system that can fight off the pathogen.

“We hypothesized that during the systemic phase of disease, Salmonella would have some way of avoiding inflammasome activation,” Brodsky said.

To identify the mechanism by which the bacteria might do this, Brodsky’s team made a library of Salmonella mutants, looking for those that might be involved in the evasion strategy.

Among the 18 genes they pinpointed were four that had been previously noted to have a role in enabling Salmonella strains to cause long-term, chronic infections.

“That was interesting because it suggested that at least a subset of those genes that might be important for long-term infection might be involved in evading or suppressing the inflammasome response,” Brodsky said.

They trained their attention on one of these four, the gene that encodes the enzyme aconitase. Aconitase, which converts citrate to isocitrate, is a key component in the metabolic process known as the citric acid or Krebs cycle. This cycle is used by all oxygen-breathing organisms to convert sugar into energy and to produce important molecules for cell growth.

When the aconitase gene was mutated, the inflammasome known as NLRP3 was highly activated, leading researchers to believe that the normal version of aconitase might do the opposite, inhibiting the inflammasome. Moreover, when the researchers infected mice with a strain of Salmonella that had a mutated version of aconitase, the rodents were able to clear the infection, likely due to the inflammasome being activated. This infection led to increased levels of inflammation in the mice’s tissues.

The Penn-led team also wanted to see whether other components of the citric acid cycle might be involved in inflammasome activation. They found that mutating Salmonella genes that encode two other players in the cycle, the enzymes isocitrate dehydrogenase and isocitrate lyase, also led to higher activation of the NLRP3 inflammasome.

In their normal state, these enzymes break down citrate. Thus the study’s results point to the possibility that the immune system may activate the inflammasome in response to the presence of citrate or some byproduct of citrate. Supporting this idea, the researchers found that Salmonella strains lacking the enzyme citrate synthase, which produces citrate, led to a reduced inflammatory response.

“We think bacteria might be exporting citrate because it would otherwise prevent the bacteria from growing,” Brodsky said. “It’s possible that the export of citrate might be triggering the inflammatory response. Our work fits into this emerging idea that bacterial metabolites might be recognized by various components of the immune system for the purpose of either negatively or positively regulating immune responses.”

The scientists believe that it’s possible that host cells put together two pieces of information to trigger an immune response, first recognizing signaling of a Toll-like receptor, which responds to structures that are common across many microbes, and then sensing bacterial products, like elevated levels of citrate, being produced inside the cell itself.

Brodsky and colleagues are now working to develop a chicken vaccine based on an attenuated strain of Salmonella that would trigger both “arms” of the inflammatory response, possibly involving an aconitase mutant. Such a vaccine would ideally more closely replicate a natural infection, protecting the animals against infection.

“We get Salmonella from chickens that are chronically infected,” Brodsky said, “so, if you could prevent or limit chronic infection of chickens, that would be a nice way to limit Salmonella in the food supply.”

Timeline PhotosThe First Tuesday Lecture has been RESCHEDULED for Tuesday, March 24, at 6:30 pm in Alumni Hall, due to the weather. Dr. Emilie Setlakwe will describe a “typical” day in the life of a veterinarian in New Bolton Center’s Neonatal Intensive Care Unit during her talk “Tales from the NICU.”

Timeline PhotosThe First Tuesday Lecture has been RESCHEDULED for Tuesday, March 24, at 6:30 pm in Alumni Hall, due to the weather. Dr. Emilie Setlakwe will describe a “typical” day in the life of a veterinarian in New Bolton Center’s Neonatal Intensive Care Unit during her talk “Tales from the NICU.”

In recognition of National Kidney Month in March, Penn Vet’s Ryan Hospital reminds pet owners that animals can suffer from a range of kidney ailments, including kidney failure, toxicity, and infection.

Timeline PhotosIt's National Pig Day! Pictured is Dr. Ines Rodriguez, staff veterinarian at New Bolton Center's Swine Teaching and Research Unit, with two of our new piglets. Learn more: http://www.vet.upenn.edu/about/campuses/new-bolton-center-campus/centers-laboratories/research-laboratory/swine-teaching-and-research-unit

February 28 is Rare Disease Day, to raise awareness with policy makers and the public of rare diseases and their impact on the lives of patients.

Penn Vet researcher Dr. Charles Vite and his team have developed a treatment for Niemann Pick Disease type C, sometimes referred to as “childhood Alzheimer’s” because of the progressive mental and physical decline seen in the children it afflicts.

3-D printing helps get local dog back on all fourswww.local8now.comFor millions of Americans - getting a knee brace or a prosthetic limb is part of life; but it may surprise you to know that new technology is making it possible for our cats and dogs to get new paws.

Penn Vet is currently recruiting dogs for a clinical trial evaluating the role of the intestinal microbiome in dogs with chronic gastrointestinal problems.

Dogs with chronic symptoms such as diarrhea and/or vomiting may be eligible. All initial diagnostics and standard-of-care treatment during the study period (2 to 8 weeks) are included free of charge.

Timeline PhotosDr. Thomas Parsons and Penn Vet's Swine Teaching and Research Center are featured in a two-part NBC-TV story by investigative reporter Bob Segall in Indianapolis about sow housing. http://www.wthr.com/story/28182789/gestation-crate-controversy-indiana-pig-farmers-face-growing-pressure
Pig producers are coming under increasing pressure to change the industry's standard gestation crates. The "Penn gestation" loose-housing model created and researched at New Bolton Center is an alternative being adopted by farmers across the nation.

Only 2 working spots left for the Principals of K9 Learning Workshop! Register now to reserve your spot!

Timeline PhotosPlease join us next Tuesday, March 3, at 6:30 pm for the First Tuesday Lecture by Dr. Emilie Setlakwe, who will describe a “typical” day in the life of a veterinarian in New Bolton Center’s Neonatal Intensive Care Unit during her talk “Tales from the NICU.”
http://www.vet.upenn.edu/about/news-and-events/press-releases/article/new-bolton-center-first-tuesday-lecture-march-3-tales-from-the-nicu

The renovations of the Ryan Hospital lobby are coming along wonderfully. They put up a new sign! And we have sliding doors!

Timeline PhotosAssociate Dean Dr. Corinne Sweeney describes the history and the importance of New Bolton Center's unique “pool recovery” system, designed for horses to awake safely from anesthesia. Dedicated 40 years ago, the pool system, created at New Bolton Center, was the first-of-its-kind, a critical innovation in veterinary surgery. Today, the updated recovery pool continues to be an integral tool used by our equine orthopedic surgeons for patients with leg fractures. Read the New Bolton Post story: http://www.vet.upenn.edu/about/news-and-events/publications/new-bolton-post/winter-2015/pool-recovery-story

Penn Vet is offering the he Veterinary Exploration Through Science (VETS) program this summer for both college and high school students (11th and 12th graders). This is a day program of one week sessions. The program has been created for students who are interested in the science of veterinary medicine.

Timeline PhotosHappy Chinese New Year in this Year of the Goat! We love goats at New Bolton Center. Many of the patients in our Neonatal Intensive Care Unit are mama goats and their kids. Learn more about our NICU: http://www.vet.upenn.edu/veterinary-hospitals/NBC-hospital/services/neonatal-intensive-care

Should pets be allowed on Amtrak trains?

Lawmakers want Amtrak to allow small pets on trains, and the idea is gaining support.

Dr. James Serpell was a guest on Science Friday to talk about dog behavior generalizations. Dr. Serpell created his C-BARQ assessment tool to see whether those generalizations were really true. While he found some common traits among breeds, he also found some variation that might be caused by the behavior of human owners.

This two-day old Chihuahua pup is being cared for in Ryan Hospital's Emergency Service. One of our residents is feeding her every two hours!

Why Your Dog's Paws Smell Like Corn Chipsvetmedicine.about.comWhat should you do if you notice that your dog's feet have an odor, often described as smelling like corn chips or old popcorn? Read this FAQ to find out more about what is commonly termed

Dr. Brittany Watson and Penn Vet students held cardiology lessons for Netter Center Pipeline students from Sayre High School. They learned basic CPR, listened to a heart murmur and compared circulatory systems from various species.

Not only is today Valentine’s Day, but it is also National Donor Day, which focuses on five points of life: organs, tissue, marrow, platelets, and blood. Penn Vet has two donor programs that are important to saving pets’ lives, one of which is our blood donor program.

Blood transfusions can be critical, life-saving procedures. Blood loss through trauma or toxins can quickly lead to severe anemia and possibly death, an outcome that can be averted through the administration of blood transfusions. The Penn Animal Blood Bank manages a large volunteer blood donor program to meet the transfusion needs of the patients at Ryan Hospital.

Not only is today Valentine’s Day, but it is also National Donor Day, which focuses on five points of life: organs, tissue, marrow, platelets, and blood. Penn Vet has two donor programs that are important to saving pets’ lives, one of which is our kidney transplant program.

The Feline Renal Transplantation Program at Penn Vet was initiated in 1998 by Dr. Lillian R Aronson. She has since performed about 150 kidney transplants. Kidney transplantation is a treatment option for renal failure and the goal is to provide a good quality of life for a cat that would otherwise be unable to survive.